The study of genes that influence cancer susceptibility is a rapidly evolving field. This proposal is focused on identifying and characterizing novel modifier loci that influence the development of cancer in the gastrointestinal tract. The system we have chosen involves the tumor suppressor gene, Adenomatous Polyposis Coli (APC). Mutations in APC cause inherited and sporadic colorectal cancers. ApcMin mice have a mutation in the homologue of the APC gene and develop multiple adenomas throughout their small and large intestines. QTL studies identified a locus, Modifier of Min (Mom 1), that dramatically modifies ApcMin-induced tumor number and size. We and others have reported that the secretory type II Phospholipase A2 (Pla2g2a) gene is responsible for at least a part of the Mom1 phenotype. While it was clear that other modifier loci are present, they were unable to be identified due to segregation of the Mom1 locus in these crosses. To further dissect genetic modifier pathways, we constructed reciprocal congenic strains by exchanging the Mom1 region between C57BL6/J and C3H/HeJ mice. These strains resulted in the usually susceptible B6 mice containinga resistant Mom1 allele and similarly, the resistant C3H mice containing a susceptible Mom1 locus. QTL analysis has now revealed the presence of 5 novel modifier regions. We propose to isolate and characterize the most potent modifiers identified between the B6-C3H reciprocal congenic strains. We will develop congenic resources to study the action of the new Mom# loci. In addition, we will refine the genetic location of each Mom# locus, using positional and candidate gene approaches to identify the gene(s) responsible for Mom# phenotypes. Finally, we will perform several biological assays to gain further insight into the molecular mechanisms underlying Mom# function. The studies outlined here will ultimately lead to insights regarding the predictive value of these modifier genes in tumor prevention and response to treatment, as well as provide avenues for novel chemopreventive agents. We believe that "an ounce of prevention is worth a pound of cure". Our research is designed to find factors that can predict which people are at-risk for developing colorectal cancer. By studying these factors, we hope to be able to develop new ways to help prevent cancers from developing in the first place.